The present invention relates to O-substituted 6-methyltramadol derivatives, processes for their production, medicaments containing these compounds, and the use of O-substituted 6-methyltramadol derivatives for the production of medicaments for treating pain, and methods for treating pain using the medicaments.
The treatment of chronic and non-chronic pain conditions is very important in medicine. There is therefore a universal need for highly effective pain treatments. The urgent need for a patient-oriented and targeted treatment of chronic and non-chronic pain conditions, which is understood to include the successful and satisfactory treatment of pain on the part of the patient, is documented in the large number of scientific studies that have recently appeared in the field of applied analgesia and in basic research relating to nociception.
Conventional opioids such as morphine are highly effective in treating severe to extremely severe pain. Their use is however limited by the known side effects such as respiratory depression, vomiting, sedation, constipation and development of tolerance. Also, they are less effective in treating neuropathic or incidental pain afflicting in particular tumor patients.
An object on which the present invention is based was accordingly to provide new analgesically effective substances that are suitable for treating pain, in particular acute but also chronic and neuropathic pain.
The present invention accordingly provides O-substituted 6-methyltramadol derivatives of the general formula I 
wherein
R is
H; C1-3-alkyl that is saturated or unsaturated, branched or unbranched, unsubstituted or substituted; CH3xe2x80x94C4-6-cycloalkyl, C4-6-cycloalkyl or thiophenyl;
optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular of the enantiomers or diastereomers, in an arbitrary mixture ratio; in the prepared form or in the form of their acids or bases or in the form of their salts, in particular physiologically compatible salts, or in the form of their solvates, in particular the hydrates.
The substances according to the invention exhibit a pronounced analgesic action.
Within the context of the present invention alkyl radicals and cycloalkyl radicals are understood to be saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons that may be unsubstituted or singly or multiply substituted. In this connection C1-2-alkyl denotes C1- or C2-alkyl, C1-3-alkyl denotes C1-, C2- or C3-alkyl, C1-4-alkyl denotes C1-, C2-, C3- or C4-alkyl, C1-5-alkyl denotes C1-, C2-, C3-, C4 or C5-alkyl C1-6-alkyl denotes C1-, C2-, C3-, C4-, C5- or C6-alkyl, C1-7-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, C1-8-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7 or C8-alkyl, C1-10-alkyl, denotes C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-. C9- or C10-alkyl and C1-8-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-. C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. In addition C3-4-cycloalkyl denotes C3- or C4-cycloalkyl, C3-5-cycloalkyl denotes C3-, C4- or C5-cycloalkyl, C3-6-cycloalkyl denotes C3-, C4-, C5- or C6-cycloalkyl, C3-7-cycloalkyl denotes C3-, C4-, C5-, C6- or C7-cycloalkyl, C3-8-cycloalkyl denotes C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C4-5-cycloalkyl denotes C4- or C5-cycloalkyl, C4-6-cycloalkyl denotes C4-, C5- or C6-cycloalkyl, C4-7-cycloalkyl denotes C4-, C5-, C6- or C7-cycloalkyl, C5-6-cycloalkyl denotes C5- or C6-cycloalkyl and C5-7-cycloalkyl denotes C5-, C6- or C7-cycloalkyl. The term cycloalkyl also includes singly or multiply, preferably singly, unsaturated cycloalkyls, as long as the cycloalkyl does not form an aromatic system. The alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl(2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, but also CHF2, CF3, CH2OCH3 or CH2OH.
In connection with alkyl and cycloalkyl the term xe2x80x9csubstitutedxe2x80x9d within the context of the present invention denotesxe2x80x94unless expressly defined otherwisexe2x80x94the substitution of at least one (optionally also several) hydrogen atom(s) by F, Cl, Br, I, NH2, SH or OH, and the terms xe2x80x9cmultiply substitutedxe2x80x9d and xe2x80x9csubstitutedxe2x80x9d in the case of multiple substitution denote that the substitution takes place on different as well as on the same atoms multiply with the same or different substituents, for example triple substitution on the same C atom as in the case of CF3, or at different positions as in the case of xe2x80x94CH(OH)xe2x80x94CHxe2x95x90CHxe2x80x94CHCl2. Particularly preferred constituents in this connection are F, Cl and OH. With regard to cycloalkyl, the hydrogen atom may also be replaced by OC1-3-alkyl or C1-3-alkyl (in each case singly or multiply substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF3 or ethoxy.
The term (CH2)3-6 is understood to denote xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, and the term (CH2)1-4 is understood to denote xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94etc.
The term xe2x80x9caryl radicalxe2x80x9d is understood to mean ring systems with at least one aromatic ring but without any heteroatom in any of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which may be unsubstituted or singly or multiply substituted.
The term xe2x80x9cheteroaryl radicalxe2x80x9d is understood to mean heterocyclic ring systems with at least one unsaturated ring that may contain one or more heteroatoms, such as nitrogen, oxygen and/or sulfur, and which may also be singly or multiply substituted. Examples of the group of heteroaryls that may be mentioned include furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.
In connection with aryl and heteroaryl, the term xe2x80x9csubstitutedxe2x80x9dxe2x80x94unless expressly stated otherwisexe2x80x94denotes the substitution of the aryl or heteroaryl by OH, F, Cl, Br, I, NH2 SH, CF3, CH2F, CHF2, CN, NO2, C1-6-alkyl (saturated), C1-6-alkoxy or C2-6-alkylene.
The term salt is understood to mean any form of the active constituent according to the invention which adopts an ionic form or is charged and is coupled to a counterion (a cation or an anion), and may be present in solution. The term is also understood to include complexes of the active constituent with other molecules and ions, in particular complexes that are complexed via ionic interactions. In particular the term is understood to mean physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids.
The term physiologically compatible salts with cations or bases is understood within the context of the present invention to mean salts of at least one of the compounds according to the inventionxe2x80x94such as when deprotonated acidxe2x80x94as an anion, with at least one cation, preferably an inorganic cation, that are physiological compatible, especially when used in humans and/or other mammals. Particularly preferred are the salts of alkali and alkaline earth metals, but also with NH4+, and in particular mono- or di-sodium, mono- or di-potassium, magnesium or calcium salts.
The term physiologically compatible salt with anions or acids is understood within the context of the present invention to mean salts of at least one of the compounds according to the inventionxe2x80x94such as when protonated, for example on the nitrogen atomxe2x80x94as a cation with at least one anion, especially a physiologically compatible anion, when used in humans and/or other mammals. In the context of the present invention the term is particularly understood to denote the salt formed with a physiologically compatible acid, namely salts with inorganic or organic acids that are physiologically compatible, especially when used in humans and/or other mammals. Examples of physiologically compatible acids include: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydrolxcex6-benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, xcex1-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The hydrochloride salt is particularly preferred.
In a preferred embodiment of the invention, in the O-substituted 6-methyltramadol derivatives of formula I
R is
H; C1-3-alkyl that is saturated or unsaturated, unbranched, unsubstituted or singly substituted, preferably with OCH3; xe2x80x94CH3xe2x80x94C4-6-cycloalkyl or C4-6-cycloalkyl that is saturated and unsubstituted; thiophenyl that is unsubstituted;
preferably R is
H, xe2x80x94CH3, xe2x80x94C2H5, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94Cxe2x89xa1CH; cyclobutyl, cyclopentyl, xe2x80x94CH3-cyclobutyl or thiophenyl, in each case unsubstituted;
in particular R is
H, xe2x80x94CH3, xe2x80x94C2H5, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94Cxe2x89xa1CH; cyclobutyl, cyclopentyl or CH3-cyclobutyl, in each case unsubstituted.
In a further preferred embodiment of the invention, in the O-substituted 6-methyltramadol derivatives of formula I, R is hydrogen.
In yet another preferred embodiment of the invention the O-substituted 6-methyltramadol derivatives are selected from the following group
2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol,
3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclo-hexyl)-phenol,
2-dimethylaminomethyl-1-(3-ethoxyphenyl)-6-methylcyclohexanol,
1-(3-allyloxyphenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,
1-(3-cyclopentyloxyphenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,
2-dimethylaminomethyl-1-[3-(2-methoxyethoxy)-phenyl]-6-methylcyclohexanol,
1-(3-cyclobutylmethoxyphenyl)-2-dimethylamino-methyl-6-methylcyclohexanol,
1-(3-cyclobutoxyphenyl)-2-dimethylaminomethyl-6-methylcyclohexanol,
2-dimethylaminomethyl-1-(3-ethynyloxyphenyl)-6-methylcyclohexanol, and
2-dimethylaminomethyl-6-methyl-1-[3-(thiophen-2-yloxy)-phenylcyclohexanol.
Preferably, the O-substituted 6methyltramadol derivative of formula I is selected from
2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methylcyclohexanol or
3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclo-hexyl)-phenol, and in particular is
3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclo-hexyl)-phenol.
The compound of formula I may be in the form of a racemate, a pure stereoisomer, in particular a pure enantiomer or diastereomer. The compound of formula I may also be in the form of mixtures of stereoisomers, in particular mixtures of enantiomers or diastereomers, in an arbitrary mixture ratio. The compound of formula I may be in the represented form, or in the form of an acid or base, or in the form of a salt, in particular a physiologically compatible salt, or in the form of a solvate, in particular a hydrate. Preferably, the compound of formula I is in the form of a hydrochloride, a bishydrochloride or a sodium salt.
In another preferred embodiment of the invention the O-substituted 6-methyltramadol derivatives according to the invention are present in a stereoisomeric form according to formula Ia: 
In yet another preferred embodiment of the invention the O-substituted 6-methyltramadol derivatives according to the invention are the (RS,RS,RS) racemate, the (xe2x88x92)-(S,S,S) or (+)-(R,R,R) enantiomer; or the (RS,SR,RS) racemate of 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)-phenol, preferably the (xe2x88x92)-(S,S,S) or (+)-(R,R,R) enantiomer of 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)-phenol, in particular the (xe2x88x92)-(S,S,S) enantiomer; or (xe2x88x92)-(1S,2S,6S)-3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)-phenol,
preferably in the form of a free base; or in the form of a salt, preferably a physiologically compatible salt, in particular the hydrochloride salt; or in the form of a solvate, in particular a hydrate.
The substances according to the invention are toxicologically harmless, and are suitable as a pharmaceutically active constituent in pharmaceutical compositions. The invention accordingly also provides medicaments containing at least one compound of formula I, as well as optionally suitable additives and auxiliary substances and/or optionally further active constituents.
The medicaments according to the invention may contain in addition to at least one O-substituted 6-methyltramadol derivative according to the invention, suitable additives and/or auxiliary substances, such as carrier materials, fillers, solvents, diluents, colorants and/or binders, and may be administered as liquid medicament forms in the form of injection solutions, droplets or juices, or as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of the auxiliary substances, etc., as well as the amounts thereof to be used depend on whether the medicament is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes. For oral administration, preparations in the form of tablets, sugar-coated pills, capsules, granules, drops, juices and syrups are suitable, while for parenteral, topical and inhalative application, solutions, suspensions, readily reconstitutable dry preparations as well as sprays are suitable. O-substituted 6-methyltramadol derivatives according to the invention in a depxc3x4t form, in dissolved form or in a plaster, optionally with the addition of agents promoting skin penetration, are suitable percutaneous application preparations. Orally or percutaneously usable preparation forms may provide for a delayed release of the O-substituted 6-methyltramadol derivatives according to the invention. In principle further active constituents known to a person ordinarily skilled in the art may be added to the medicaments according to the invention.
The amount of active constituent to be administered to the patient varies depending on the patient""s weight, type of application, medical indication for use and the severity of the condition. Normally 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg of at least one O-substituted 6-methyltramadol derivative according to the invention are applied.
The invention furthermore provides for the use of an O-substituted 6-methyltramadol derivative according to the invention for the production of a medicament for treating pain, in particular neuropathic, chronic or acute pain; or for treating migraine, hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold-induced allodynia, or inflammatory or post-operative pain.
The invention additionally provides a process for treating a person or non-human mammal that requires treatment of medically relevant symptoms by administration of a therapeutically effective dose of an O-substituted 6-methyltramadol derivative according to the invention, or a medicament according to the invention. The invention relates in particular to suitable processes for treating pain, in particular neuropathic, chronic or acute pain, including migraine, hyperalgesia and allodynia, especially thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold-induced allodynia, or for treating inflammatory or post-operative pain.
The invention moreover provides a process for preparing an O-substituted 6-methyltramadol derivative according to the invention as illustrated in the following description and examples. The present invention accordingly also provides a process for preparing an O-substituted 6-methyltramadol derivative according to the invention, in which 2-dimethylaminomethyl-6-methylcyclohexanone according to formula II is reacted with an organometallic compound of formula III 
in which Z denotes Li and R has one of the meanings described above for formula I, to form a compound of formula I.
General Preparation of the Compounds According to the Invention
Reactions described in the literature (e.g., R. C. Larock, Comprehensive Organic Transformations, 2nd Edition, Wiley, N.Y. 1999 and literature cited therein) as well as experimental procedures known to the ordinarily skilled person in the art were used for the syntheses.
O-derivatized 6-methyltramadol compounds of formula I can be prepared by a process which is characterized in that 2-dimethylaminomethyl-6-methylcyclohexanone II is reacted with an organometallic compound of formula III 
in which Z for compounds in which Rxe2x89xa0H denotes MgCl, MgBr, MgI or Li, and for compounds in which Rxe2x95x90H denotes Li, and R has one of the meanings given above for formula I, to form a compound of formula I.
Alternatively, the compounds of formula I can also be obtained by reacting 3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)-phenol (formula IV) with a halogen compound of formula V, in which X denotes chlorine or bromine, with a base such as potassium tert.-butylate, sodium hydride, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, or sodium hydrogen carbonate, in a solvent such as tetrahydrofuran or dimethylformamide at a temperature preferably between 0xc2x0 C. and the reflux temperature of the solvent. The reaction may also be carried out using potassium hydroxide or sodium hydroxide in a solvent such as methanol or ethanol. 
3-(2-dimethylaminomethyl-1-hydroxy-6-methylcyclohexyl)-phenol of formula IV may also be obtained by reacting 2-dimethylaminomethyl-1-(3-methoxyphenyl)-6-methyl-cyclohexanol, (obtained by reacting 2-dimethylaminomethyl-6-methylcyclohexanone of formula II, with 3-bromoanisole and magnesium in a Grignard reaction), with a selective ether cleavage reagent such as diisobutylaluminium hydride, boron trichloride, boron tribromide or methionine.
The reaction with diisobutylaluminium hydride is preferably carried out in an aromatic hydrocarbon, for example toluene, at a temperature between 60xc2x0 C. and 130xc2x0 C. (Synthesis 1975, 617; DBP 2409990, 2409991, and Chem. Abstr. 84, 59862 (1974)).
In addition, 3-(2-dimethylaminomethyl-1-hydroxy-6-methyl-cyclohexyl)-phenol of formula IV can also be obtained from 1-(3-benzyloxyphenyl)-2-dimethylaminomethyl-6-methyl-cyclohexanol by reductive debenzylation. The debenzylation is carried out in the presence of platinum or palladium absorbed as catalyst on a support such as activated charcoal in the presence of hydrogen in a solvent such as acetic acid or a C1-4-alkyl alcohol at pressures of 1 to 100 bar and temperatures of 20xc2x0 to 100xc2x0 C.
The reaction of dimethylaminomethyl-6-methylcyclohexanone II with a Grignard compound of formula III in which Z denotes MgCl, MgBr or MgI, or with an organolithium compound of formula III, in which Z denotes lithium, may be carried out in an aliphatic ether, for example diethyl ether, or tetrahydrofuran, or a mixture thereof, at temperatures between xe2x88x9270xc2x0 C. and +60xc2x0 C. Compounds of formula III in which Z denotes Cl, Br or I can be obtained by halogen-lithium exchange by reaction with for example an n-butyllithium/hexane solution.
Dimethylaminomethyl-6-methylcyclohexanone of formula II can be prepared by processes known in the literature (Houben-Weylxe2x80x94Methoden der Organischen Chemie, E21b, 1995, pp. 1925-1929; M. Tramontini, L. Angiolini, Mannich Bases, Chemistry and Uses, CRS Press, 1994 and literature cited therein).
For example, dimethylaminomethyl-6-methylcyclohexanone of formula II can be obtained from 2-methylcyclohexanone by reaction with dimethylamine hydrochloride and formaldehyde in glacial acetic acid, water or in a C1-4-alkyl alcohol, or by reaction with dimethylammonium methylene chloride in acetonitrile under acetyl chloride catalysis (Synthesis 1973, 703; Tietze, Eicher, Reaktionene und Synthesen im Organisch Chemischen Praktikum, Thieme Verlag, Stuttgart, 1991, p. 189).
The diastereomeric dimethylaminomethyl-6-methylcyclo-hexanones formed in the aminomethylation reaction can be obtained in a pure diastereomeric form either by column chromatography separation or by fractional crystallization of their hydrochlorides from an organic solvent such as 2-butanone or acetone. Separation is also possible via chiral columns and/or with chiral reagents, preferably tartaric acid or substituted tartaric acid.
Salt Formation
Compounds of formula I can be converted by a method well-known to one of ordinary skill in the art into their salts with physiologically compatible acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydrolxcex6-benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, xcex1-lipoic acid, acetylglycine, acetylsalicylic acid , hippuric acid and/or aspartic acid. The salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl esters of acetic acid, acetone and/or 2-butanone or also water. For the production of the hydrochlorides, trimethylchlorosilane in aqueous solution is moreover suitable.
The invention is described in more detail hereinafter by means of examples, without however being restricted thereto.